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Associations of the seven-repeat (7R) allele of the human dopamine receptor D4 (DRD4) gene
with both the personality trait of novelty seeking and attention deficit/hyperactivity disorder
have been reported. Recently, on the basis of the unusual DNA sequence organization of the
DRD4 7R 48-bp tandem repeat (VNTR), we proposed that the 7R allele originated as a rare
mutational event that increased to high frequency by positive selection. We now have
resequenced the entire DRD4 locus from 103 individuals homozygous for 2R, 4R, or 7R
variants of the VNTR, a method developed to directly estimate haplotype diversity. DNA from
individuals of African, European, Asian, North and South American, and Pacific Island
ancestry were used. 4R/4R homozygotes exhibit little linkage disequilibrium (LD) over the
region examined, with more polymorphisms observed in DNA samples from African
individuals. In contrast, the evidence for strong LD surrounding the 7R allele is dramatic, with
all 7R/7R individuals (including those from Africa) exhibiting the same alleles at most
polymorphic sites. By intra-allelic comparison at 18 high-heterozygosity sites spanning the
locus, we estimate that the 7R allele arose prior to the upper Paleolithic era ( 40,000 50,000
years ago). Further, the pattern of recombination at these polymorphic sites is the pattern
expected for selection acting at the 7R VNTR itself, rather than at an adjacent site. We propose
a model for selection at the DRD4 locus consistent with these observed LD patterns and with
the known biochemical and physiological differences between receptor variants.
*
Address for correspondence and reprints: Dr. Robert K. Moyzis, Department of Biological Chemistry, College of
Medicine, Sprague Hall, University of California at Irvine, Irvine, CA 92697. E-mail: rmoyzis@uci.edu
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Introduction
The human dopamine receptor D4 (DRD4) gene, located near the telomere of chromosome 11p,
exhibits an unusual amount of expressed polymorphism (Lichter et al. 1993; Ding et al. 2002; Grady
et al. 2003). Much of this variation is the result of length and of SNP changes in a 48-bp tandem
repeat (VNTR) in exon 3, encoding the third intracellular loop of this D2-like receptor. Alleles
containing 2-11 repeats (2R-11R) have been found, with over 67 different haplotype variants
uncovered to date (Ding et al. 2002; Grady et al. 2003). The three most common variants 2R, 4R,
and 7R represent >90% of the observed population allelic diversity. In most geographical locations,
the 4R allele is the most common, whereas 2R and 7R allele frequencies vary widely (Chang et al.
1996; Ding et al. 2002).
The functional significance of these length/sequence changes in the DRD4 protein, in a region
that couples to G proteins and mediates intercellular cAMP levels, has been studied extensively
(Asghari et al. 1995; Jovanovic et al. 1999; Oak et al. 2000). In particular, the 7R variant exhibits a
blunted ability to reduce cAMP levels, in comparison with that of the common 4R variant (Asghari et
al. 1995). The DRD4 protein is expressed in a number of brain regions, with a high level of
expression in the prefrontal cortex, a region thought to be involved in cognition, attention, and other
higher brain functions (Oak et al. 2000). Significantly, DRD4 knockout mice display better
performance on complex motor tasks; are supersensitive to cocaine, ethanol, and methamphetamine;
and exhibit reduced exploration of novel stimuli (Rubinstein et al. 1997; Dulawa et al. 1999). Taken
together, these results are consistent with the proposal that DRD4 receptors act as inhibitors of
neuronal firing, especially in the prefrontal cortex (Oak et al. 2000; Rubinstein et al. 2001).
On the basis of these biochemical and physiological observations, a number of investigations have
looked for associations between behavioral phenotypes and particular alleles of this highly variable
gene (Faraone et al. 2001; Swanson et al. 2001; Klugar et al. 2002; Grady et al. 2003). Although
some studies have suggested that the DRD4 7R allele might be associated with the personality trait of
novelty seeking (MIM 601696) (Klugar et al. 2002), the most reproduced association is between the
7R allele and attention deficit/hyperactivity disorder (ADHD) (MIM 126452) (Faraone et al. 2001;
Swanson et al. 2001; Grady et al. 2003). ADHD is the most prevalent disorder of childhood ( 5%
incidence) and is defined by symptoms of developmentally inappropriate inattention, impulsivity,
and hyperactivity. The 2-fold greater prevalence of the DRD4 7R allele in ADHD probands ( =
1.9), calculated from a recent meta-analysis (Faraone et al. 2001), indicates that this allele is
associated with a significant fraction (25% 50%) of the attributable genetic risk for the disorder
(Grady et al. 2003).
Elsewhere, we showed by DNA resequencing/haplotyping of 600 DRD4 VNTRs, which
represented a worldwide population sample, that the origin of most haplotype variants could be
explained by simple one-step recombination/mutation events (Ding et al. 2002). In contrast, the 7R
allele is not related simply to the other common alleles, differing by >6 recombinations/mutations.
This unusual sequence architecture of the 7R VNTR, suggesting it arose as a rare mutational event,
led to exploratory measures of linkage disequilibrium (LD) between the 4R and 7R alleles. Large
discrepancies between allele ages, estimated from low intra-allelic variability and high population
frequency, are taken as evidence that selection has increased the frequency of an allele beyond that
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expected by chance (Slatkin and Rannala 2000; Tishkoff et al. 2001; Ding et al. 2002; Sabeti et al.
2002; Bamshad and Wooding 2003; Swanson 2003). Strong LD was found between the 7R allele and
four surrounding DRD4 polymorphisms, suggesting this allele is significantly "younger" than the
common 4R allele. Our preliminary estimates placed the most recent common ancestor of the DRD4
7R allele around the time of major human population expansion out of Africa and the appearance of
radical new technology (the upper Paleolithic era) (Harpending and Rogers 2000; Ingman et al. 2000;
Underhill et al. 2000; Ding et al. 2002). We speculated that these events may be related to the
appearance of and selection for the DRD4 7R allele (Ding et al. 2002).
If the DRD4 7R allele arose recently and underwent strong positive selection, why is it currently
disproportionately represented in individuals diagnosed with ADHD? One possibility is that an
adjacent polymorphism in strong LD with the 7R VNTR is actually associated with ADHD or may
be the target of selection. We have argued that selection for an adjacent site was unlikely, given the
distinct and unusual DNA sequence organization of the DRD4 7R allele itself (Ding et al. 2002), but,
owing to the high density of SNPs in the human genome, selection for an adjacent site remained a
possibility. Obviously, even if the DRD4 VNTR is the site of selection, strong LD in the region could
have carried an adjacent ADHD-predisposing polymorphism along with it. Such "hitch-hiking"
events should be common (Fay and Wu 2000), again, given the high density of SNPs in human DNA
(International SNP Map Working Group 2001).
Alternatively, the biochemical and physiological properties of the DRD4 protein (discussed
above) suggest a more direct relationship. We have proposed that the 7R ADHD association is an
example consistent with the Common Variant Common Disorder hypothesis (Risch and Merikangas
1996; Grady et al. 2003), in which common predisposing alleles result in deleterious effects only
when combined with other environmental/genetic factors. We have speculated that the same traits
that may be selected for in individuals with a DRD4 7R allele also may predispose behaviors that are
deemed inappropriate in the typical classroom setting and hence diagnosed as ADHD (Ding et al.
2002; Grady et al. 2003). In this environmental-mismatch hypothesis (Hartman 1993; Jensen et al.
1997), the DRD4 7R subset of individuals diagnosed with ADHD is assumed to have a different,
evolutionarily successful behavioral strategy, rather than a disorder. It is also possible, however, that
DRD4 7R, although selected for in human populations, could have deleterious effects when
combined with genetic variants in other genes (Ding et al. 2002; Grady et al. 2003).
To clarify some of these issues, we report an extensive analysis of polymorphisms surrounding the
DRD4 VNTR, by genomic resequencing. Remarkably, we show that the 7R allele exhibits strong LD
worldwide, in geographic locations as diverse as sub-Sahara Africa and South American rainforests.
By intra-allelic comparison at 18 high-heterozygosity sites spanning the locus, we refine the age
estimate of the most recent 7R-allele common ancestor to 40,000 50,000 years. Further, the pattern
of inferred recombination at these sites is the pattern expected for selection acting at the VNTR itself,
rather than at an adjacent polymorphism.
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culture, and DNA purification have been described elsewhere (Chang et al. 1996; Ding et al. 2002;
Grady et al. 2003). All individuals gave their informed consent before their inclusion in this study,
which was carried out under protocols approved by the human subjects committees at the
participating institutions. The geographical and ethnic origins of the 103 individuals who were part of
this study, grouped by genotype, are:
1. DRD4 4R/4R 24 European (11 unspecified European, 5 Irish, 3 English, 3 German, 1 Greek,
and 1 Italian), 20 African (11 Biaka, 3 Chagga, 3 Mbuti, 2 Hausa, and 1 African American),
and 7 Asian (5 Han Chinese and 2 Japanese);
2. DRD4 7R/7R 19 American (6 Karitiana, 5 Ticuna, 4 Maya, and 4 Surui), 16 European (6
unspecified European, 3 European/Hispanic, 2 Irish, 1 Dane, 1 Druze, 1 English, 1 German,
and 1 Italian), 6 African (2 Biaka, 2 Hausa, 1 African American, and 1 Chagga), and 2 Pacific
(both Nasioi); and
3. DRD4 2R/2R 6 Asian (5 Han Chinese and 1 Yakut) and 3 European (1 Russian and 2
unspecified European).
Of these individuals, 20 (19%) (15 European, 4 Asian, and 1 African) were ADHD probands
(Grady et al. 2003), including 1 2R/2R, 14 4R/4R, and 5 7R/7R genotypes.
Primate DNA was obtained from 5 chimpanzees (Pan troglodytes), 5 bonobos (P. paniscus), and
5 western lowland gorillas (Gorilla gorilla gorilla), all unrelated individuals.
PCR Amplification and DNA Sequencing
The entire DRD4 allelic region was PCR amplified as three overlapping fragments (totaling 6.3
kb), which cover positions 140173 to 146480 in GenBank accession number AC 021663. The current
Human Genome Project (HGP) assembly contains a 9-kb unordered fragment containing the DRD4
locus (from BAC RP11-496I9), but the terminal DRD4 upstream region of this contig contains 1.9 kb
of Alu DNA (International Human Genome Sequencing Consortium 2001). Forward and reverse
primers for these amplifications were 140173F1(5 -GTGGTCGCAGACATCTTGG-3 ), 142075R1 (5
-TAGACGAAGAGCGGCAGCA-3 ), 142057F2 (5 -TGCTGCCGCTCTTCGTCTA-3 ), 145072R2
(5 -ATGCTGCTGCTCTACTGGG-3 ), 144901F3 (5 -CCTGCTGTGCTGGACGCCCT-3 ), and
146480R3 (5 -TAGTCGGAGAAGGTGTCCTG-3 ). PCR amplification and the removal of excess
primer and dNTP was as described elsewhere (Ding et al. 2002; Grady et al. 2003). Additional
primer sequences for forward and reverse sequencing of the DRD4 amplification products are
available on our Web site. DNA cycle sequencing on automated sequencers ABI 3100 and 3700 was
conducted as described elsewhere (Riethman et al. 2001; Ding et al. 2002; Grady et al. 2003).
Analysis of Sequence Data
Analysis of sequence data was aided by Phred, Phrap, Polyphred, and Consed (Nickerson et al.
1997). The collection and editing of SNPs into a relational database was done via an in-house
software package we designated "SNPMAN" (Grady et al. 2003). Visual displays of SNP data were
performed using visual genotyping (VG) (Nickerson et al. 1998).
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Results
The unusual nature of the sequence architecture of the DRD4 7R VNTR, suggesting it arose as a
recent rare mutational event (Ding et al. 2002), led us to determine whether differences in LD exist
between 4R and 7R chromosomes. We resequenced 6,307 bp of contiguous DNA surrounding the
DRD4 VNTR from 103 individuals (1.5 Mb total) chosen from previous screenings (Chang et al.
1996; Ding et al. 2002; Grady et al. 2003) as homozygous for the VNTR (4R/4R, 7R/7R, and 2R/2R)
(fig. 1). DRD4 loci from 51 4R/4R individuals, 43 7R/7R individuals, and 9 2R/2R individuals were
resequenced. 7R/7R and 2R/2R individuals were highly oversampled in comparison to their
frequency in the population (Chang et al. 1996; Ding et al. 2002). This approach was developed as a
direct and efficient method to estimate the haplotype diversity surrounding the putative ancestral 4R
allele, in comparison to the recent 7R allele.
Figure 1 Polymorphism distribution at the DRD4 locus. Using VG (Nickerson et al.
1998), 70 DRD4 polymorphisms are displayed, with variants aligned along the horizontal
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axis. Approximate locations of the variants along the DRD4 locus (GenBank AC021663)
are indicated by blue lines reaching to the diagrammatic representation of the gene. In this
representation, exon positions are represented by blocks (yellow = noncoding; orange =
coding; +1 = translation start), and the positions of Alu repetitive sequences are
represented by pointed blue blocks. The positions of a 120-bp upstream duplication and
the 48-bp VNTR in exon 3 are indicated by green triangles. A 288-bp site (designated -809
G/A to -521 C/T) at the promoter region that contains an anomalously high number of
SNPs is indicated. These SNPs exhibit little difference in 4R vs. 7R frequency. Individuals
(on the vertical axis) are grouped by VNTR length (4R/4R, 7R/7R, and 2R/2R) and by
geographic origin (African, European, etc.) as indicated. Homozygotes for the allele with
the highest relative frequency (common allele) are indicated by blue squares,
homozygotes for alternative (rare) alleles by yellow squares, and heterozygotes by red
squares. The 7R/7R and 2R/2R individuals were greatly oversampled in comparison to
their population frequency; hence, common and rare alleles were defined by the
frequencies in a randomly sampled population. SNP and genotype information is available
at dbSNP and the authors' Web site.
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Carlson et al. 2003) (fig. 1). By resequencing this same genomic region in 15 primate genomes, the
likely ancestral variant could be determined unambiguously for most SNP pairs. Of the most
common variants, 76% (13/17) were inferred to be ancestral in origin (table 1), with one SNP
(144,842) having both variants in primate DNAs. Four of the most common variants in the
population were "human specific" (table 1). Of the observed polymorphisms in tight LD with the 7R
VNTR, 41% (7/17) were the rarer human-specific allele (fig. 1; table 1).
Table 1
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contain a variant in the first intron (142,115; marked by an asterisk [*] in fig. 1) found only in one 4R
individual of African ancestry, suggesting a common origin and expansion for these 2R alleles.
Under the assumption of random assortment of variants, the probability that these radically
different LD patterns (fig. 1) could have occurred by chance is infinitesimally small, requiring
multiple low-probability events (10-3 10-43). Indeed, it would be difficult to construct alleles that
differ more. Calculations of allele age made on the basis of the relatively high worldwide population
frequency of the DRD4 2R, 4R, and 7R alleles suggest that these alleles are ancient (>300,000
500,000 years old) (Ding et al. 2002). On the other hand, calculations of allele age on the basis of
the observed intra-allelic variability suggest that the 7R allele is 10-fold "younger" (table 1).
Although it is useful (and common) to refer to the "allele age" calculated from intra-allelic
variability, it should be noted that such calculations more accurately estimate the most recent
common ancestor (Slatkin and Rannala 2000). Such large discrepancies between the allele ages
calculated by these two methods are usually taken as evidence that strong selection has increased the
frequency of the allele to higher levels than expected by random genetic drift (Slatkin and Rannala
2000; Ding et al. 2002). The absolute values of these estimates are greatly affected by the
assumptions on which they base their computations for example, the assumed recombinationfrequency. For the calculations in table 1, we have used the extreme values of estimates of the
recombination frequency observed for the telomeric regions of human chromosomes (including 11p)
(Kong et al. 2002). All 18 high-heterozygosity DRD4 SNPs used to estimate allele age yield
comparable results (table 1). This suggests that the average of these values (40,000 50,000 years) is
a reasonable current estimate of the most recent common ancestor for DRD4 7R. The use of the
extremes of assumed recombination frequency (Age 1 and Age 2) and of generation time, SD,
yields an estimate of 20,000 81,000 years (table 1) for the limits of allele age. The proposed origin of
the 2R allele as a 7R allele derivative (fig. 1) indicates that it also must be a young allele. The
discrepancy between the observed high frequency of the 2R allele (especially in Asian populations)
and its recent 7R origin (fig. 1) suggests that it, too, has increased in frequency by positive selection.
Although these observed LD differences are the best indicator of selection at this locus, other
statistical tests of selection also confirm this hypothesis. These ad hoc tests condense information
into a summary statistic and therefore lose information present in LD displays (fig. 1); nevertheless,
they have been widely applied in prior work and are presented for comparison (Kreitman 2000). One
of the most commonly applied tests, Tajima's D, compares the difference between two estimators of
neutrality: (1) the number of segregating sites in a sample and (2) the average number of nucleotide
differences between two sequences (Tajima 1989). Tajima's D applied separately to 4R/4R and
2R/2R homozygote data did not reach statistical significance, whereas 7R/7R homozygote data
yielded a statistically significant negative value (-2.117, P < .05), usually interpreted as an indicator
of selection (Kreitman 2000). Tajima's D applied to all 103 individuals yielded a statistically
significant value indicating selection (-1.827, P < .05). The application of Fu and Li's D* and of Fu
and Li's F* (Fu and Li 1993), other widely used tests for selection, to the total population sample also
yielded statistically significant indications of selection (-2.958, P < .05 and -2.975, P < .02,
respectively). As discussed above, the application of these tests to nonrandom data sets, such as ours,
may be inappropriate. However, calculating the same statistics on a modified data set (see "Material
and Methods"), in which the frequency of 2R, 4R, and 7R alleles was comparable to that expected
from random population sampling (Ding et al. 2002), still yielded statistically significant signs of
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Discussion
In this study, we have expanded our LD analysis of the DRD4 gene by resequencing the entire
locus in 2R, 4R, and 7R homozygous individuals. This method was chosen as an accurate and
efficient approach to determine the comparative LD of two alleles, requiring little statistical
manipulation to infer haplotype differences. By use of this approach (fig. 1), the pattern of LD
surrounding the DRD4 4R allele is the pattern expected for an ancient gene locus (300,000 500,000
years old), in which haplotype diversity is greatest in African populations and more restricted outside
Africa (Slatkin and Rannala 2000; Tishkoff and Verrelli 2003).
In contrast, the evidence for strong LD surrounding the 7R allele is dramatic (fig. 1). Such
worldwide LD for a single human allele is remarkable. For example, in one of the best-characterized
examples of selection in humans, the frequencies of low activity alleles of glucose-6-phosphate
dehydrogenase are highly correlated with the prevalence of malaria, yet many regional variants have
been selected for (Tishkoff et al. 2001; Sabeti et al. 2002). There is no worldwide "malaria resistant"
variant, presumably because the introduction of agriculture 10,000 years ago (and the Plasmodium
parasite) selected for independent regional mutations (Tishkoff et al. 2001; Sabeti et al. 2002). By
intra-allelic comparison at 18 high-heterozygosity sites, we can estimate that the DRD4 7R allele
arose prior to the upper Paleolithic era ( 40,000 50,000 years ago, with likely limits of 20,000
81,000 years ago) (table 1).
We emphasize that this estimate is only as reliable as the assumptions on which its calculation is
based, and further studies will likely refine this number. However, allele-age estimates calculated by
alternative methods (for example, by assuming a fixed mutation rate on Y-chromosome DNA; see
Ingman et al. [2000], Slatkin and Rannala [2000], and Underhill et al. [2000]) are also subject to
considerable uncertainty. Hence, all such estimates should be considered provisional. In particular, it
should be noted that no theory has been developed to predict the average age of a selected allele in a
growing population and that strong selection may alter the calculated age in such a population.
Current estimates suggest, however, that such an effect is not dramatic (Slatkin and Rannala 2000).
Regardless of the absolute origin-date for the DRD4 7R allele, the unusual worldwide LD observed
for this allele (fig. 1) suggests either that it predates the last major out-of-Africa human expansion or
that there has been significant backflow of this allele from a non-African origin into Africa. Evidence
for such a backflow has been presented for other loci (Cruciani et al. 2002). Further population
sampling may resolve these possibilities; however, a pre-out-of-Africa 7R origin seems more likely.
Elsewhere, we have argued that population bottlenecks and local admixture cannot explain the
observed bias toward nonsynonymous amino-acid changes, the unusual VNTR structure, and the
high LD surrounding the DRD4 locus (Ding et al. 2002). Further, proposing unusual genetic
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this site in primate DNA, suggesting that this region is a hotspot for such changes. We suggest,
therefore, that high frequency gene conversion might explain this homogenization. Small hotspots for
gene conversion have been proposed to exist at many loci in the human genome (Ardlie et al. 2001).
The overall strong LD associated with the 7R allele continues upstream of this anomalous region (fig.
1). It is possible that the association of a polymorphism, in this upstream region, with ADHD
(McCracken et al. 2000) reflects this strong LD with the 7R VNTR. The small sample of ADHD
probands (20 individuals), included in the current analysis (fig. 1), did not exhibit any variations in
adjacent polymorphisms different from the remaining 2R/2R, 4R/4R, and 7R/7R individuals.
A Model
Extensive biochemical analyses of DRD4 protein variants have been conducted (Asghari et al.
1995; Jovanovic et al. 1999; Oak et al. 2000). The 7R protein has a blunted response for cAMP
reduction, requiring a three-fold increase in dopamine concentration for reductions comparable to the
4R protein (Asghari et al. 1995). This "suboptimal" response of the 7R allele to dopamine was
hypothesized to underlie its association with the personality trait of novelty seeking (Klugar et al.
2002) and with ADHD (Swanson et al. 2001). It was suggested that the inhibitory neurons utilizing
the DRD4 7R receptor would require increased dopamine for "normal" function (Swanson et al.
2000). Such increased dopamine levels were hypothesized to be the result of risk-taking behavior (in
the case of novelty seeking) or methylphenidate (in the case of ADHD). Methylphenidate is thought
to act by binding to the dopamine transporter and raising the levels of dopamine at the synapse
(Swanson et al. 2001; Volkow and Swanson 2003).
We propose a simple model integrating the known biochemical, physiological, and genetic data
regarding the common DRD4 alleles (fig. 3). The 4R allele appears to be the most common allele
throughout most of human prehistory. This ancestral allele has the fewest amino acid-changing
variants, implying strong purifying selection (Ding et al. 2002). The 7R allele arose as a rare
mutation that significantly blunted the receptor's response to dopamine (fig. 3). We hypothesize,
however, that this blunted response led to behaviors that were selected for in certain environments,
and the 7R allele increased in frequency (starting 40,000 50,000 years ago). Rather than spreading
in a purely directional pattern, the 7R allele, we have proposed, exists as a balanced polymorphism
(Ding et al. 2002). Evidence for this model includes: (1) the less likely probability that a purely
directional selection will be observed in the process of spreading (Harpending and Rogers 2000;
Ding et al. 2002); (2) the high worldwide allele frequencies of 2R, 4R, and 7R alleles, suggesting
selection for all alleles (Chang et al. 1996; Ding et al. 2002); (3) the strong nonhomologous aminoacid replacement (Ka/Ks ratio >1) observed for all alleles (2R, 4R, and 7R) (Ding et al. 2002); (4) the
unusual geographic distribution of 2R and 7R alleles, not consistent with strong directional selection
but consistent with "deme" variation (Chang et al. 1996; Kreitman 2000; Ding et al. 2002); and (5) a
site frequency distribution of adjacent variants not consistent with directional selection but consistent
with balanced selection (i.e., a deficit of singletons and an excess of intermediate frequency variants;
see fig. 1). Such a proposed multiallelic adaptive strategy is likely common (Sinervo and Lively
1996; Harpending and Rogers 2000), and is predicted by evolutionary game theory (Smith 1982).
Figure 3 A diagrammatic model for DRD4 variant selection. DRD4 2R, 4R, and
7R protein variants are shown diagrammatically, aligned on a scale of relative
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efficiency for cAMP reduction. These values were calculated from the data of
Asghari et al. (1995), normalized to 4R = 1.0. Haplotype nomenclature (i.e., 1-2-34) appears as proposed elsewhere (Ding et al. 2002). The unusual derivation of the
7R allele from the ancestral 4R allele ( 40,000 50,000 years ago) and its increase
in prevalence are indicated by red to turquoise arrows. The subsequent derivation
of the 2R allele from a 7R/4R recombination is indicated by turquoise to blue
arrows.
The genetic data suggest that most 2R alleles are 7R derivatives and likely had limited (yet
multiple) origins (fig. 3). Interestingly, the 2R variant also has a blunted cAMP response, but one that
is midway between those of the 4R allele and 7R allele (fig. 3). We hypothesize that individuals with
2R alleles exhibit behaviors "intermediate" between those manifested by individuals with 4R and 7R
alleles. This "nonlinear" response (i.e., cAMP reduction capability is not linearly related to DRD4
VNTR-repeat length) (Asghari et al. 1995; Jovanovic et al. 1999) is consistent with the genetic
evidence and suggests a typical biochemical "optimum" strategy (fig. 3). We have suggested that this
biochemical/genetic data implies that characterizing individuals by DRD4 4R/4R versus non-4R
genotype may be more appropriate for testing various gene/behavior associations (Grady et al. 2003).
What could be the behavioral differences that are selected for? By observing current genetically
influenced differences in human personality (summarized in Bouchard and Loehlin [2001]), it has
been suggested that resource-depleted, time-critical, or rapidly changing environments might select
for individuals with "response ready" adaptations, whereas resource-rich, time-optimal, or littlechanging environments might select against such adaptations (Jensen et al. 1997). We have
speculated that such a "response ready" adaptation might have played a role in the out-of-Africa
exodus and that allele frequencies of genes associated with such behavior certainly would be
influenced, subsequently, by the local cultural milieu (Ding et al. 2002; Harpending and Cochran
2002). For example, the wide variation in allele frequency in different geographic locations (Chang
et al. 1996) is expected for balanced polymorphisms, where individual demes have different
equilibrium states based on local conditions (Kreitman 2000). Consistent with this "response ready"
behavior hypothesis is the significantly better performance of DRD4 knockout mice on tests of
complex coordination (Rubinstein et al. 1997) and the observed faster reaction times exhibited by
individuals with ADHD who have a 7R allele, in comparison to non-7R individuals (Swanson et al.
2000; Langley et al. 2004). Counterbalancing the presumed benefits of faster reaction times may be
the increased risk of cortical hyperexcitability (including convulsions) exhibited by DRD4 knockout
mice (Rubinstein et al. 2001). It is possible that the trade-offs between faster reaction time and
hyperexcitability are influencing the hypothesized balanced selection at this locus.
In this model, the 4R variant has been honed for hundreds of thousands of years to function
optimally, whereas the new 7R and 2R variants are suboptimal yet confer a behavioral advantage in
some environments. Though the "response ready" hypothesis was proposed as an environmental
adaptation, sexual selection has long been proposed as another source of human variation (Darwin
1871). For example, there is ample evidence that polygyny has been a historical norm in most human
societies and that some degree of risk-taking behavior is an expected path to reproductive success
(for reviews, see Betzig [1993], Buss [1999], and Fehr and Fischbacher [2003]). We suggest that
sexual selection, influenced by the local cultural norms and by the response to behaviors affected by
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these VNTR variants, has contributed to the unusual DRD4 allelic distribution.
In particular, we suggest that this model helps explain the unusual geographic distribution of the
7R allele, which is at low frequency in Asian populations but at high frequency in the Americas
(Chang et al. 1996; Ding et al. 2002). The 2R and 7R alleles are genetically and functionally related,
each exhibiting suboptimal dopamine-signaling, in comparison with that of 4R alleles (fig. 3). One
possibility is that the 7R allele never existed at high frequency in Asian populations, but its "role" in
the hypothesized balanced-selection system was filled by the "comparable" 2R allele. This
hypothesis implies that there are no major selective differences acting on this locus in Asian
populations, that it is merely a functionally irrelevant deme variation. Consistent with this hypothesis
is our recent study indicating that the 2R allele frequency in Chinese ADHD probands is increased by
an amount comparable to the 7R allele increase observed in European-ancestry ADHD probands
(Leung et al. 2004). Alternatively, the frequency of the 7R allele in Asian populations might at one
time have been higher. In this hypothesis, after the initial migration into Asia, the 7R frequency was
reduced while the derivative 2R allele frequency increased, implying the two alleles may not be
"functionally" equivalent. One can only speculate as to what environmental/cultural factors could
have influenced such a replacement. Most Asian cultures, however, have a much longer recorded
history of effective societal reproductive intervention/selection than those of European and African
cultures (Betzig 1993), and hence are more likely to have influenced gene frequency by such a
mechanism.
In either hypothesis, the severe bottlenecks North and South American ancestry populations
underwent during their migration from Asia can explain adequately their high incidence of 7R
alleles. Either the proposed strong selection for the 7R allele in certain "response-ready"
environments (above) or random chance could influence allele frequency in such small migrating
populations.
Although this speculative model (fig. 3) is consistent with available genetic, biochemical, and
physiological data, only further work can test, refine, and modify these ideas. Clearly, further genetic,
biochemical, and behavioral studies are needed. The evidence for selection acting at the DRD4 locus
is strong, however (figs. 1 and 2), and challenges us to determine the specific mechanism driving it.
Regardless of the ultimate details, is it reasonable to think that a single gene variation can modify
human behavior yet be shaped by cultural diversity? We argue that just such single-gene changes
regulating complex social behavior have been identified in other social organisms (Krieger and Ross
2002). We see no reason to think humans should be exempt from similar Darwinian selection
(Darwin 1871). The evolutionary payoff of an individual's behavior in complex human societies,
obviously, will depend strongly on the reaction of others to that behavior (Betzig 1993; Buss 1999;
Ding et al. 2002; Harpending and Cochran 2002; Fehr and Fischbacher 2003). We suggest the
exciting possibility that the DRD4 locus is a prime candidate for investigating such gene and culture
interactions.
Acknowledgments
This work was supported by grant MH60660 (to R.K.M.) from the National Institute of Mental
Health.
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Electronic-Database Information
Accession numbers and URLs for data presented herein are as follows:
z
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Figure 1
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Polymorphism distribution at the DRD4 locus. Using VG (Nickerson et al. 1998), 70 DRD4
polymorphisms are displayed, with variants aligned along the horizontal axis. Approximate locations
of the variants along the DRD4 locus (GenBank AC021663) are indicated by blue lines reaching to
the diagrammatic representation of the gene. In this representation, exon positions are represented by
blocks (yellow = noncoding; orange = coding; +1 = translation start), and the positions of Alu
repetitive sequences are represented by pointed blue blocks. The positions of a 120-bp upstream
duplication and the 48-bp VNTR in exon 3 are indicated by green triangles. A 288-bp site
(designated -809 G/A to -521 C/T) at the promoter region that contains an anomalously high number
of SNPs is indicated. These SNPs exhibit little difference in 4R vs. 7R frequency. Individuals (on the
vertical axis) are grouped by VNTR length (4R/4R, 7R/7R, and 2R/2R) and by geographic origin
(African, European, etc.) as indicated. Homozygotes for the allele with the highest relative frequency
(common allele) are indicated by blue squares, homozygotes for alternative (rare) alleles by yellow
squares, and heterozygotes by red squares. The 7R/7R and 2R/2R individuals were greatly
oversampled in comparison to their population frequency; hence, common and rare alleles were
defined by the frequencies in a randomly sampled population. SNP and genotype information is
available at dbSNP and the authors' Web site.
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Table 1
FREQUENCY
ALLELE AGE (years)
(%)
POLYMORPHISM
ALLELES
DISTANCE
TO EXON 3
VNTR
140,438
L/S (120
bp)*
-4143
61.9
90.8**
33,361
66,715
140,582
G/del
-3999
95.0
13.9**
19,175
39,557
140,692
T/C
-3889
94.7
15.1**
22,269
44,653
140,892
T/C
-3689
70.0
95.4
22,558
45,119
141,507
C/T
-3074
73.7
97.7
14,884
29,771
142,426
G/A
-2155
90.0
97.7
28,961
57,922
143,578
A/del
-1003
78.4
98.80
28,493
56,989
143,766
C/A*
-815
77.5
4.6
37,539
75,078
143,862
G/del
-719
95.0
2.3**
17,037
34,075
144,842
G/A
261
88.7
1.6
34,865
69,731
144,862
G/C
281
87.9
1.6**
32,686
65,373
145,239
del/G*
658
43.8
2.3
31,637
63,221
145,295
T/C
714
79.0
2.3**
20,690
41,381
145,353
del/G
772
41.7
2.3**
27,615
55,181
145,684
A/C*
1103
69.4
3.5
23,457
46,915
146,041
T/C
1460
42.1
3.8
26,699
53,397
146,056
T/C
1475
57.9
96.3
26,989
53,966
146,293
C/A
1712
44.7
4.6
28,187
56,367
26,505
(SD=6,112)
53,078
(SD=12,139)
Average
4R/4R
7R/7R
Age 1
Age 2
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Figure 2
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Frequencies of DRD4 7R recombinant chromosomes. The graph shows the observed percentage of
recombinant chromosomes at the 18 SNPs (table 1) versus the distance from the 7R VNTR. The
curve is an empirically determined least-squares fit to the data. The diagrammatic representation of
the DRD4 locus is as described in fig. 1.
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Figure 3
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A diagrammatic model for DRD4 variant selection. DRD4 2R, 4R, and 7R protein variants are shown
diagrammatically, aligned on a scale of relative efficiency for cAMP reduction. These values were
calculated from the data of Asghari et al. (1995), normalized to 4R = 1.0. Haplotype nomenclature
(i.e., 1-2-3-4) appears as proposed elsewhere (Ding et al. 2002). The unusual derivation of the 7R
allele from the ancestral 4R allele ( 40,000 50,000 years ago) and its increase in prevalence are
indicated by red to turquoise arrows. The subsequent derivation of the 2R allele from a 7R/4R
recombination is indicated by turquoise to blue arrows.
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